Lung cancer and idiopathic pulmonary fibrosis (IPF) are linked diseases, with IPF patients being at a seven-fold increased risk of lung cancer. Both of these diseases can be characterized by dismal patient outcomes and the lack of effective disease modifying therapies. The identification of common disease progressing substances may yield novel therapeutic targets. We propose that the neutrophil-derived serine proteinase, neutrophil elastase (NE), is such a target. NE drives disease progression of both lung adenocarcinoma and lung fibrosis in mouse models via similar mechanisms. NE impacts the target cell in cancer and fibrosis, the tumor cell and fibroblast, respectively, in two distinct ways. First, NE induces tumor cell and fibroblast proliferation. Second, NE alters the behavior of tumor cells and fibroblasts, generating tumor cell epithelial to mesenchymal transition (EMT), and driving myofibroblast differentiation. Both of these processes are intimately linked to advanced disease in the setting of lung cancer and IPF. This proposal will identify the mechanisms by which NE induces cell proliferation and alters cell behavior in hopes to identify novel therapeutic targets common to both diseases. Additionally, these studies should validate NE itself, as a valid therapeutic target for patients inflicted with lung cancer and/or IPF. PUBLIC HEALTH RELEVANCE: Lung cancer and idiopathic pulmonary fibrosis are "linked," diseases, meaning that patients with IPF are at an increased risk to subsequently develop lung cancer. The outcomes for both of these diseases are dismal, with combined mortality reaching nearly 200,000 American lives each year. We have identified an inflammatory cell derived protein called neutrophil elastase that promotes disease progression in both IPF and lung cancer. The purpose of this proposal is to establish neutrophil elastase as a legitimate therapeutic target for patients with lung cancer and/or pulmonary fibrosis.